Association of vitamin K with insulin resistance and body composition.

Abstract: Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Osteocalcin (OC), a vitamin K-dependent protein, may have a role in the regulation of glucose metabolism and adiposity. To evaluate this role of OC in humans, one also needs to take into consideration the effect of vita... read moremin K (VK). Because OC depends on VK for carboxylation, and thus function, the percentage of OC that is not carboxylated (%ucOC) has been used as a measure of VK status, with lower %ucOC representing higher circulating VK. In mice, the uncarboxylated form of OC (ucOC) is active in glucose metabolism and body composition. The data in humans are equivocal. Despite its dependence on VK, very few human studies examining the association between OC and insulin resistance (IR) or diabetes risk have taken VK status into account. To address this shortcoming, we examined the associations between VK, OC, IR and body weight in three well-characterized cohorts. Our specific aims were: 1: To determine if intentional weight loss is associated with a decrease in the carboxylation of OC in post-menopausal women when VK intake is held constant, 2: To determine if increased carboxylation of OC through VK supplementation is associated with lower markers of IR in younger and older men and women, and 3: To determine the cross-sectional associations between circulating VK concentrations and markers of IR in older men and women. For specific aim 1, data were obtained from healthy post-menopausal women (n=71) undergoing a twenty-week weight loss program. Measures of body weight, body fat percentage, and serum OC forms were assessed before and after the intervention. All participants lost weight (-10.9±3.9 kg) and body fat (-3.9±2.0 %), but their weight-loss was not associated with changes in any form of serum OC (all p>0.31). For specific aim 2, data were obtained from 42 healthy younger (age= 18-40y) and older (age= ±65y) men and women who received a VK supplement for 21 days. Circulating measures of OC, VK, and markers of IR were assessed before and after supplementation. With VK supplementation, circulating uncarboxylated OC (ucOC) decreased (pre= 4.4±3.0, post= 1.1±2.1 ng/mL, p<0.001) with no concomitant change in the homeostatic model of insulin resistance (HOMA-IR, p=0.78). No significant correlation between any form of OC (total OC (tOC), ucOC or %ucOC) and HOMA-IR was observed (p>0.12). For specific aim 3, data were obtained from a large multi-center cohort of community dwelling older men and women (n= 932). Circulating measures of VK and IR were measured. Serum lipids were also measured since VK is transported on triglyceride-rich lipoproteins. A trend for higher plasma VK to be associated with lower measures of HOMA-IR was observed in men with normal triglycerides only (β= -0.077, p=0.08). No significant associations were noted for women, consistent with prior literature. The approach was limited to secondary analysis. However, the data from three independent cohorts were consistent in that ucOC was not associated with measures of IR or weight loss in community-dwelling men and women. In contrast, there was a trend for higher circulating VK to be associated with lower HOMA-IR cross-sectionally, particularly in older men with normal triglycerides. Carefully designed studies are required to define the role of VK in the regulation of glucose metabolism in humans. read less